It is well known that resistance to viral infections and the ability to generate protective immunity following vaccination declines with age. While most of us have been vaccinated and are probably life-long immune to many common viral diseases, we have recently become more aware that emerging infectious diseases are possible, that pandemics with new strains of known viruses such as influenza are likely to occur, and that highly pathogenic microorganisms could be used as weapons. In each of these cases, the non-immune elderly would be at a much higher risk of disease and death than the young. Because the elderly represent a sizable proportion of the world population, understanding the reasons and trying to overcome the consequences of the age- dependent loss of natural and acquired resistance to viral diseases is of major public health interest. However, a direct detailed analysis of the loss of resistance to viral diseases in humans is not possible and appropriate animal models must be used. Mousepox is a frequently lethal disease of the mouse caused by the Orthopoxvirus (OPV) ectromelia virus (ECTV), a disease with remarkable resemblance to human smallpox (caused by the OPV variola virus, VARV) and monkeypox (caused by the homonym OPV). Some strains of mice, such as C57BL/6 (B6), are known to be naturally resistant to mousepox. However, we have recently found that B6 mice lose this resistance as they age. Thus, comparing the immune functions in response to primary ECTV infection of young and aged B6 mice offers an excellent model to understand the age-dependent loss of resistance to viral disease. Furthermore, because mousepox can be prevented with the smallpox vaccine, our new finding opens the opportunity to determine whether aged mice can be protected by vaccination. The overarching goal of this exploratory project will be to pinpoint the specific immune functions affected by age that correlate with the loss of natural and acquired resistance to mousepox. The long-term objective for this project is to understand the underpinnings behind any defective function discovered during this exploratory phase. Furthermore, we intend to find new methods to manipulate the immune response to restore resistance and improve vaccine efficacy in aged mice as a first approach to improve vaccine efficacy in elderly people. [unreadable] [unreadable] [unreadable]